PHARMACOKINETICS OF FULL-LENGTH AND 2-DOMAIN TISSUE FACTOR PATHWAY INHIBITOR IN COMBINATION WITH HEPARIN IN RABBITS

Tissue factor pathway inhibitor (TFPI) is a feed back inhibitor of the initial activation of the extrinsic pathway of coagulation. In humans , injection of heparin results in a 2-6 fold increase in plasma TFPI a nd recent studies suggest that TFPI may be important for the anticoagu lant activity of heparin. Full length (FL) TFPI, but not recombinant t wo-domain (2D) TFPI, has a poly cationic C-terminus showing very stron g heparin binding. Therefore, we have investigated if heparin affects the pharmacokinetics of TFPI with and without this C-terminus. FL-TFPI (608 U/kg) and 2D-TFPI (337 U/kg) were injected intravenously in rabb its with and without simultaneous intravenous injections of low molecu lar weight heparin (450 anti-XaU/kg). Heparin decreased the volume of distribution and the clearance of FL-TFPI by a factor 10-15, whereas t he pharmacokinetics of 2D-TFPI were unaffected by heparin. When hepari n was administered 2 h following TFPI the recovery of FL-TFPI was simi lar to that found in the group receiving the two compounds simultaneou sly, suggesting that the releasable pool of FL-TFPI is removed very sl owly in the absence of circulating heparin.